Premature birth, or the delivery of an infant before 37 weeks gestation, is the result of preterm labor and it affects approximately 10% of pregnancies world-wide with growing numbers now at 12% in the United States. In spite of advances in technology, prematurity results in substantial morbidity and mortality as high as 80% in infants born earlier than 33 weeks gestation in developing countries. Surviving infants have high rates of cognitive delay, cerebral palsy, chronic lung disease, blindness and deafness. The enormity of this problem, which disproportionately affects the poor and minority groups, is devastating in its impact on individuals, families, and society and compels investigations into etiologies that may lead to improvements in treatment and prevention. While some specific causes of prematurity are recognized, such as twin pregnancies and cervical incompetence, the majority are "spontaneous". Potential initiators include infection, poor nutrition, and inherited factors. Twin and family studies suggest that genetic factors underlie 40% of this risk and the single best predictor for preterm delivery is a previous preterm birth. While there are many approaches to identifying causal mechanisms in complex traits such as prematurity, genetic investigations afford the opportunity to not only validate previously suspected etiologies but to identify unanticipated factors. A major challenge in studying genetic factors in prematurity is that the risk case is not explicitly defined as it might be either the mother and her uterus, the infant/placental unit, or the two together. We have assembled a team of investigators including obstetricians, pediatricians, quantitative geneticists, and molecular biologists to undertake a comprehensive approach to identify genetic causes of prematurity. We will use a family collection scheme in which either the infant or the mother can be studied as a potential case and a powerful three generation collection approach coupled to genome-wide searches to identify some of the multiple genes likely contributing to prematurity and its secondary outcomes. Our group has worked together for many years and will use our extensive experience in clinical ascertainment, molecular genetics and statistical approaches for gene identification. Specific aims include: I. Case identification and characterization. II. Candidate gene evaluation. III. Genome-wide scans using both linkage and linkage disequilibrium. IV. Fine-mapping for gene identification. The outcome will be confirmation (or rejection) of previously suspected factors, identification of new genetic contributions, and the establishment of a platform that will enable us to move quickly into studies of environmental covariates, biological mechanisms and clinical trials for prevention and treatment.